Metabolic status and vascular endothelial structure in obese hypertensive patients treated with non-pharmacological therapies: A systematic review and meta-analysis

Objective This meta-analysis aimed to evaluate the efficacy of non-drug treatment on metabolism and vascular endothelium in obese hypertension. Methods Relevant publications were searched in the PubMed, Embase, and Cochrane Library databases for clinical studies on the effects of non-pharmacological treatments in obese hypertensive patients published from inception to April 2022. After searching and screening the literature, information was extracted, and the quality of the literature was evaluated by the investigators. Data processing was performed using Rev Man 5.3 statistical analysis software, while the TSA 0.9 software was used for sequential analysis of blood pressure and endothelial-related indicators. Results A total of 8 literature articles with 480 patients were included. The analysis showed that non-pharmacological treatment effectively reduced systolic blood pressure, diastolic blood pressure, heart rate, body weight, body mass index, glucose levels, soluble intercellular adhesion molecule 1, triglycerides, triglycerides, Low-density lipoprotein. For tumor necrosis factor α, soluble vascular cell adhesion molecule 1, high-density lipoprotein, C-reactive protein, high-sensitive C-reactive protein, and total antioxidant status by dietary supplements mainly. In contrast, no significant treatment effect was observed for Endothelin-1. Sequential analysis of the trial showed definitive evidence for improvement in blood pressure and inflammation. Conclusion Non-pharmacological treatment of obese hypertensive patients may reduce blood pressure, body weight, and blood glucose, control inflammatory factor release and improve vascular endothelium to some extent.


Introduction
Inclusion criteria (1) Study content: Randomized controlled trial (RCT) reporting on the effects of non-drug treatment on hypertensive vascular endothelium in obese patients and safety systematic review. (2) Study subjects: obese patients diagnosed with hypertension, including baseline demographics such as gender, age, race, etc. (3)Intervention measures: The control groups were given conventional treatment or other types of interventions. The test groups were given any treatment such as drugs under investigation, life-style changes, dietary habits, various psychological and behavioral habits, exercise for weight loss, or rehabilitation. (4)The outcome measures should includeat least one of the following. Primary outcome measures: systolic blood pressure(SBP), diastolic blood pressure(DBP), Heart rate, body weight, body mass index (BMI), glucose levels, forearm blood flow (FBF), soluble intercellular adhesion molecule 1 (sICAM-1)levels, soluble vascular cell adhesion molecule 1(sVCAM-1) levels, endothelin-1 (ET-1)levels, tumor necrosis factor α(TNF-α)levels, Secondary Outcome Measures: Low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides(TC), triglycerides(TG), C-reactive protein(CRP), high-sensitive C-reactive protein(hs-CRP), total antioxidant status (TAS).

Exclusion criteria
Studies for which the full text could not be obtained and literature which did not use any of the above-mentioned evaluation indicators were excluded. Studies with incomplete data or containing serious errors were also excluded. For duplicate publications, only the first one was retained For studies sharing the same sets of data, only the one with the most complete data was retained.

Data sources and search strategies
Relevant publications were searched in PubMed, Embase, and Cochrane Library databases. The search period spanned from database establishment to April 2022. Keywords included "Hypertension", "Weight Loss" and "randomized controlled trial", "Vascular endothelial". The search time was from database establishment to April 2022. The language of included kinds of literature was limited to English (S1 Table).

Literature screening, extraction, and quality evaluation
Two investigators independently searched and screened the literature titles and abstracts, excluding obviously irrelevant studies. The remaining pieces of literature were screened by reading the full text. In case of any disagreement, a consensus was reached with the help of a third investigator. The extracted information mainly included: the first author, publication time, patient age, gender, number of included cases, specific intervention measures, and outcome measures. The Cochrane recommended risk of bias assessment tool was used to evaluate the quality of the included pieces of literature.

Statistical processing
The Meta-analysis of the collected data was performed using Review Manager 5.3 software and sequential analysis was performed with TAS V0.9 software. The heterogeneity of the included trials was analyzed by the Q test, and the heterogeneity was judged by the I 2 test. I 2 < 50%, indicated no significant heterogeneity in the included literature, and the fixed-effect model was selected for analysis. In contrast, I 2 � 50%, indicated greater heterogeneity and the random-effect model was applied. p < 0.05was considered, statistically significant. Moreover, a funnel plot was used to evaluate publication bias. The results were then subjected to TAS.

Literature search results
A total of 1235 relevant articles were obtained after the initial search, 800 articles remained after excluding removing duplicate publications, and 39 articles were obtained after further reading the abstracts and full texts. In total, 13 articles that were not RCTs, 6 articles that were not rigorously designed, 8 animal trials, and 4 articles within consistent outcome measures were excluded. Finally, 8 pieces of literature [13][14][15][16][17][18][19][20] were included in the meta-analysis. Fig 1, illustrates the literature retrieval and flow chart.

Risk of bias
According to the risk of bias assessment tool recommended by Cochrane, there were 3 articles with low bias and 5 articles with moderate bias, as shown in Fig 2.

Basic information of included literature
Eight pieces of literature with a total of 480 subjects were included in this study, of which 262 subjects received non-drug treatment, and 218 subjects had no intervention. The patients were

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from different countries around the world. The specific main study characteristics are summarized in Table 1 below.   , p = 0.001). All analyses were performed using a random effects model, with the statistical significance set at p <0.05 (Fig 3). Therefore, this analysis demonstrated that non-pharmacological treatment was effective in reducing systolic pressure, diastolic pressure and heart rate. .00001) respectively. All analyses were performed using a random effects model, with the statistical significance set at p <0.05 (Fig 4). The results demonstrated that non-pharmacological treatment was effective in improving weight, BMI and glucose indicators in subjects.

Meta-analysis results
(III): One article [15] measured forearm blood flow in subjects, revealing an association between non-drug treatment and forearm vasodilation due to endogenous and exogenous NO donors, which attenuated the vasoconstrictor response to norepinephrine. Three pieces of literature [14,15,19] demonstrated improvements in endothelium-dependent vasodilation (EDD) of peripheral ductal arteries and resistance vessels, as well as brachial artery flow-mediated dilatation(FMD) and forearm blood flow to acetylcholine, should be improved on both sides. The improvement in vascular endothelial function may be attributed to the reduced abdominal visceral fat and the decrease in lipoprotein after weight loss, which could decrease oxidative stress and increase NO bioavailability to improve EDD.

Fig 6. Forest map secondary outcome indicators (A) TG Forest map secondary outcome indicators (B) TC Forest map secondary outcome indicators (C) HDL Forest map secondary outcome indicators (D) LDL Forest map secondary outcome indicators.
https://doi.org/10.1371/journal.pone.0279582.g006 Sequential analysis of the trial. Sequential analysis was performed on systolic blood pressure, diastolic blood pressure, TNF-α, endothelin-1, sICAM-1, and sVCAM-1. Type I error was defined at 5%, and the information axis was set as the cumulative sample size, with 80% statistical. The sample size was used as the expected information value (TSA) , Fig 9. The sequential analysis for systolic blood pressure, sICAM-1, and sVCAM-1 showed that the sample size had crossed the traditional cut-off value and TSA cut-off value at the time of study

Fig 8. Risk of bias assessment (A) Funnel plot of body weight, BMI, and blood glucose (B) Funnel plot of inflammatory factors.
https://doi.org/10.1371/journal.pone.0279582.g008 inclusion, and a positive conclusion was obtained in advance. However, the diastolic blood pressure reached the traditional cut-off value but did not reach the TSA cut-off value, suggesting a high risk of false-positive results. Therefore, these results require further randomized controlled trials for verification. In the sequential analysis of Endothelin-1, The Z curve did not intersect with the TSA cut-off or the conventional cut-off and did not reach the desired ideal sample size. This indicated that a large number of randomized controlled studies are required to confirm the effects of non-pharmacological treatment on obese hypertension and vascular endothelium.
GRADE quality evaluation. The GRADE system was used to evaluate the evidence level of various indicators, the risk of bias, consistency of results, indirectness, accuracy, and publication bias. The results showed that outcome measures of the effect of non-drug quality on hypertensive vascular endothelium in obese patients which 1 intermediate

Discussion
Both American and European guidelines suggest dietary interventions to lower blood pressure and suggest that dietary modification is one of the cornerstones to improving arterial hypertension. Improving lifestyle is also a mainstay of cardiovascular disease prevention [21,22]. The literature included in this study showed that non-drug treatment could improve blood pressure, heart rate, weight, BMI, blood glucose, inflammatory factors, and vascular endothelial markers. However, due to obese hypertensive patients often having multiple diseases, it is still necessary to investigate the therapeutic effect according to the specific circumstances of the patients. A total of 8 pieces of literature were included in this study. The meta-analysis showed that non-drug treatment is particularly effective in reducing systolic blood pressure, diastolic blood pressure, heart rate, weight, BMI, blood glucose, and other indicators in obese hypertensive patients. SICAM-1 and sVCAM-1 were also improved, while no significant difference in TNF-α and Endothelin-1 was observed between the two groups. The latter may be due to the small sample size of subjects, as the sequential analysis of the trial also suggested the need for sample size validation. The inflammatory factors all showed improvement after nondrug treatment. Nevertheless, the funnel plot suggested publication bias, which may be related to the small sample size effect, Trial sequential analysis showed that non-drug treatment had conclusive evidence in improving sICAM-1 and sVCAM-1 and reducing blood pressure.
Obesity is an independent risk factor for cardiovascular disease, and numerous studies have shown that body weight plays a crucial role in blood pressure [20]. Excessive adipose tissue distribution affects hormones levels and causes corresponding inflammatory and endothelial changes. 60% of obese hypertensive patients may be attributed to increased fat stores. Furthermore, NHANES data indicated a prevalence of 42.5% for hypertension [23,24] in obese individuals with a BMI<30 kg/m2. Studies have also demonstrated a positive correlation between BMI and the risk of hypertension, with a relatively high prevalence of hypertension in people with high BMI [25]. Obesity can lead to increased arterial stiffness and decreased vascular wall compliance [26] through the release of free fatty acids from the systemic circulation, insulin resistance, and hyperinsulinemia. The vascular endothelium dynamically maintains vascular tension, mediating angiogenesis, hemostasis, anti-oxidation, and anti-thrombosis. Endothelial dysfunction is the main pathological manifestation of cardiovascular disease, metabolic disease, and emerging infectious diseases. The release of vasodilators and the increase of vasoconstrictors are important markers of endothelial dysfunction. The mechanisms by which endothelial dysfunction leads to the development of hypertension may involve: (1) increased aortic stiffness; (2) altered vascular tension; (3)

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Metabolic status and vascular endothelial structure in obese hypertensive with non-pharmacological therapies increased oxidative and nitrosative stress; (4) increased inflammatory response; (5) increased endothelin secretion [10], and so on. In the 6 included studies, HDL, LDL, CRP, hs-CRP, TNF-α, endothelin-1, FBF, and other indicators reflected varying degrees of vascular endothelial dysfunction and changes in vascular structure.
The direct or indirect treatment cost of hypertension was 46.4 billion yuan in 2011 and is expected to increase sixfold by 2030, highlighting the importance of low-cost non-drug treatment [27,28]. Studies have shown that exercise, improvement of dietary habits, maintenance of good mood, and reduction of alcohol consumption can improve the vascular endothelium [10]. Non-pharmacological treatments have gained popularity and have been applied in various fields [29][30][31]. However, non-drug treatment has poor efficacy for hypertension patients with multiple diseases.
Limitations of the study: (1) A small number of studies was included and were limited to only those published in English, which overlooked other pieces of literature; (2) The age range of subjects was large but had a small sample size. In addition, publication bias was detected, requiring large, multicenter, high-quality clinical randomized controlled trials to verify the clinical efficacy. Therefore, further research is needed to apply the treatments in clinical practice; (3) Waist circumference, hip circumference, and waist-to-hip ratio have a more accurate prognostic predictive value than BMI and should be accurately measured in obese patients. (4) Only life-style and dietary supplements were analyzed as non-pharmacological treatments, while vegetable consumption, low-fat dairy products, and non-nutritional supplements were overlooked. (5) Relatively few studies have been performed on TNF-α, endothelin-1 and other endothelium-related indicators of hypertension. The efficacy of the non-pharmacological treatments on the vascular endothelium of obese hypertensive patients could not be evaluated accurately.

Conclusions
The literature included in this study showed that non-pharmacological treatments based on life-style and dietary supplements can improve blood pressure, heart rate, weight, BMI, blood glucose and related indicators such as inflammatory factors. Due to the small sample size of the study, it was relatively ineffective in improving the endothelium, but it gives us more caution, especially in modifying blood pressure by improving life-styles, which is more desirable, and it is worth promoting and benefiting more people initially by modifying their life-styles rather than medication. Since obese hypertensive patients often have multiple morbidities, treatment plans should be tailored on a patient-by-patient basis.
Supporting information S1 Table. Search string for PubMed, Embasa, and Cochrane Library databases. (DOCX) S1 Checklist. Reporting items for systematic review and meta-analysis (PRISMA) 2020 statement guideline.